Taste masking drug formulations

ABSTRACT

The present disclosure relates to a taste-masking microcapsule composition. The composition comprises a core portion encapsulated by a shell portion. The core portion comprises an active pharmaceutical ingredient (API) and one or more excipients. The shell portion comprises a hydrophobic matrix and a pH-responsive material. The microcapsule compositions prevent API release at the more neutral pH levels in the oral cavity, but upon exposure to pH levels of the stomach, the pH-responsive material becomes soluble thereby permitting release of the API.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of PCT/US2015/017485 filed onFeb. 25, 2015 which claims priority to U.S. Provisional Application No.61/944,152 filed on Feb. 25, 2014, which is incorporated herein byreference in its entirety.

BACKGROUND

Upwards of 79% of children discharged from pediatric hospitals areprescribed one or more medications that are designed, approved, andintended for use in adults, underscoring the need for pediatric-specificformulations. In the absence of pediatric-specific dosages, formulationsthat are both palatable (to ensure compliance) and titratable (to meetthe weight/surface area-appropriate dosage needs from neonates toadolescents), health-care providers either: (i) prescribe adult-approvedliquid formulations; or (ii) manipulate available products to createextemporaneous formulations (e.g., by crushing a tablet). Liquidsuspensions, while titratable and largely preferred by children overtablets and capsules, are often poorly palatable (i.e. liquid forms ofprednisone and ritonavir) resulting in poor compliance. Extemporaneousformulations can alter the performance including the palatability andbioavailability of the original product thereby contributing to bothpoor compliance (only 70% compliance in hospitals) and increased riskfor under and over-dosing. Free flowing drug-loaded microcapsule powderswould allow pharmacists to prepare highly palatable microcapsule liquidsuspensions to accurately dose children of all ages.

SUMMARY

The present compositions and methods are based on the discovery thatrelease profiles, bioavailability, and palatability can be preciselycontrolled by a microcapsule formulation comprising a drug-rich coreencapsulated in a pH-responsive shell. The pH-responsive shell beinginsoluble at pH levels associated with the oral cavity, but soluble atpH levels associated with stomach or other region of thegastrointestinal system thereby preventing release of the activepharmaceutical ingredient until the appropriate pH is encountered. Thedrug rich core of the microcapsule may be formulated with appropriateexcipients to permit the desired release profile, whether immediate orextended-release. Methods of producing these compositions is alsoprovided.

Thus, in one embodiment, the present composition comprises amicrocapsule having a core portion encapsulated by a shell portion. Thecore portion comprising an active pharmaceutical ingredient and anexcipient. The shell portion comprising a hydrophobic matrix and apH-responsive material.

The active pharmaceutical ingredient may comprise any agent that is usedas a therapeutic and more particularly, a therapeutic that presents afoul taste. Examples of particular active pharmaceutical ingredientsdiscussed herein include prednisone and ritonavir.

The excipient that is used with the active pharmaceutical ingredientmay, in some instances, be dependent on the properties of the activeingredient. For example, a hydrophilic excipient may be used inconnection with a hydrophobic active ingredient. Furthermore, theexcipient may be chosen to provide particular release profiles. Examplesof suitable classes of excipients include, but are not limited to waxes,lipids, polyethylene glycol (e.g. PEG 2000 and PEG 6000), polyols,stearates, and block copolymers. In particular embodiments, when theactive pharmaceutical ingredient is prednisone or ritonavir,polyethylene glycol is a suitable excipient.

The shell portion comprises a hydrophobic matrix and a pH-responsivematerial. In one particular example, the pH-responsive material isinsoluble at a pH of greater than 5.0 or are otherwise insoluble insaliva, but that are soluble at a pH of less than 5.0. In otherembodiments, the pH-responsive material may be soluble or insoluble atvarious other pH levels encountered in the gastrointestinal system basedon the desired release profile. Examples of pH-responsive materialsinclude butylated methacrylate copolymer (Eudragit® E-100 PO), aminomethacrylate copolymer, aminoakyl methacrylate copolymer,hydroxypropylmethycellulose phthalate, hypromellose phthalate,polyacrylates derivatives, and polymethacrylates derivatives.

The hydrophobic matrix component of the shell may include one or more ofglycerol fatty acid esters, high molecular weight glycols (e.g.,polyethylene glycol with a minimum of 20 repeating units), celluloseethers (e.g., ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose), cellulose esters (e.g.,cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate), poloxamers, starch, stearic acid, ceresine wax,beeswax, ozokerite, microcrystalline wax, candelilla wax, montan wax,carnauba wax, paraffin wax, cauassu wax, Japan wax, and Shellac wax.

The composition of any of the above embodiments may comprise a pluralityof microcapsules having a mean particle diameter from about 50 μm toabout 500 μm, from about 100 μm to about 400 μm, from about 150 μm toabout 300 μm, and generally about 200 μm, wherein at least about 80% ofthe microcapsules have a particle diameter within 1-25%, 2-20%, 5-15%,and generally within 10% of the mean particle diameter.

The composition of any of the above embodiments may be provided in avariety of formats including liquid suspensions, chewable tablets, andeffervescent tablets.

A method of producing the various microcapsule compositions is alsoprovided. In one embodiment, the method comprises the following steps:(1) dissolving an active pharmaceutical ingredient in ethanol to producean active pharmaceutical ingredient-ethanol mixture; (2) co-melting theactive pharmaceutical ingredient -ethanol mixture with a moltenexcipient to provide a core dispersion; (3) melting a polymer and alipid to form a shell mixture; and (4) applying the core dispersionthrough a central portion of a nozzle and simultaneously applying theshell mixture through an annular portion of the nozzle surrounding thecentral portion in the presence of vibrational excitation therebyforming the microcapsule, wherein the microcapsule comprises a coreportion and a shell portion. The method may further comprise the step ofapplying a stabilizing air stream to the nozzle as the microcapsuleexits the nozzle to reduce the diameter of the microcapsule. The methodmay be performed with any combination of active pharmaceuticalingredient, excipient, polymer, and hydrophobic matrix combinationdescribed herein for the various microcapsule compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

In addition to the drawings described below, additional drawings areprovided summarized in the presentation set out in Appendix A, attachedhereto.

FIG. 1 provides DSC thermograms of APIs and their dispersions inhydrophilic matrix. Both prednisone (A) and ritonavir (B) demonstratethat they are dispersed within the matrix in an amorphous manner, due tolack of discrete drug melting peaks. A low crystallization of drug willalso expedite dissolution once the microcapsule shell has degraded.

FIG. 2 provides light microscopy images of prednisone (A) and ritonavir(B) microcapsules according to the present disclosure. A distinct coreand shell can be seen in both types of powders.

FIG. 3 provides dissolution profiles of prednisone (A) and ritonavir (B)microcapsules of the present disclosure in neutral and acidicconditions, compared to their RLD syrup formulations. In the first 2minutes (yellow), the microcapsule formulations mitigate drug release ina neutral environment, then quickly release the API thereafter.

FIG. 4 provides dissolution profiles of ritonavir microcapusles inacidic conditions immediately after fabrication, and after storage for 4weeks at 25° C.

FIG. 5 provides dissolution profiles of prednisone (top) and ritonavir(bottom) microcapsules of the present disclosure in neutral (first 2minutes) and acidic conditions thereafter (except for Formulations 1,2,5, and 6 which were maintained under neutral conditions for theduration) compared to their respective RLD syrup formulations.

DESCRIPTION

The present disclosure generally relates to taste masking formulationsof compounds that permit accurate dosing and the ability to process intoa variety of dosing formats as well as processes for manufacturing thesame.

It is often difficult for formulation scientists to develop a dosagethat offers both a high level of taste-masking as well as immediate andcomplete release soon after the dosage form clears the oral cavity. Thisis especially true for the foulest-tasting drugs given that mosttaste-masking techniques rely on adding progressively thickertaste-masking shells to progressively reduce drug release through theshell in the oral cavity. Unfortunately, after passing through the oralcavity, this same taste-masking shell coating is a barrier to rapidrelease.

To address this problem, the present disclosure describes, in oneembodiment, a pH-responsive shell that is insoluble at the neutral pHsfound in the oral cavity, but readily dissolves at the acidic pHs foundin the stomach, thereby limiting the release of the drug-loaded coreuntil it reaches the stomach.

More generally, the present disclosure provides a composition thatcomprises a plurality of microcapsules with each microcapsule comprisinga core portion and a shell portion. The core portion comprises an activepharmaceutical ingredient (API) and an excipient. The shell portioncomprises a pH-responsive material and a hydrophobic matrix component.

The core portion is designed to maximize API loading and to permitformulation of the API that provides a rapid dissolution upon exposureto an aqueous environment. In order to meet these goals, the coreportion should include a balance between API and excipient that willprovide a finely dispersed (solid dispersion) or dissolved (solidsolution) state prior to particle hardening. The excipients utilized inthe core portion are at least in part dependent on the properties of theAPI, for example, the API's hydrophilicity or hydrophobicity. Thus, incertain embodiments, the excipients are hydrophilic. Furthermore, theexcipients, in order to maximize API loading, may promote homogenousdispersion, solubilization or the ability to complex with the API. Forexample, the excipients are selected from the group consisting of waxes,lipids, polyethylene glycol (PEG), polyols, stearates, and blockcopolymers including poloxamers and lutrols.

The API may include a variety of compounds including, but not limited tothose that are foul-tasting and generally not readily available in aformulation that allows for consistent and safe dosing formats inpediatric patients. In one specific example, the API is selected fromthe group consisting of prednisone and ritonavir. The percentage of APIin the core can be from about 1% to 100% (100% in the instance the APIitself is in the form of a liquid such as melted drug or vitamin E).Additionally, the percentage of API in the core portion can be fromabout 1% to 50%, from about 1% to 25%, and from about 1% to about 10%.In the instance the API cannot be melted or dissolved (i.e. fine drugparticles in suspension), the percentage of API in the core portion canbe equal to or less than 10%. For any of the above percentages of API,the balance of the core portion may be one or more excipients.

The shell portion is designed to promote stability by protecting thecore formulation from the storage environment and to regulate corerelease during administration to a patient. The storage environment maybe aqueous, an oil-suspending agent, or simply air with a standardhumidity content. In order to regulate release, the shell portion maycomprise materials that are responsive to specific pH ranges,temperature changes, and other unique physiochemical propertiesincluding degree of hydration or response to specific enzymes.

For the stabilizing or hydrophobic matrix component of the shellportion, suitable materials include those that are not approaching anyphase transitions at room temperatures such as waxes, lipids, and highmolecular weight copolymers. Examples of suitable hydrophobic matrixmaterials include carnauba wax, glyceril tristearate, glyceriltrimyristate, beeswax, candellila wax, stearyl alcohol, stearic acid,gylceryl monostearate, ethyl cellulose, hydroxpropylmethylcellulose,poly(ethylene glycol), sorbitan oleate, sorbitan monooleate, poloxamers,and gelatin, and various combinations thereof.

For the pH-responsive material, also referred to as the“release-responsive component,” suitable materials include those thatare soluble at pH levels encountered in the stomach (<5.0), butinsoluble at pH levels encountered in the oral cavity (>5.0) orotherwise insoluble in saliva. Examples of such pH-responsive materialsinclude methacrylate copolymer, butylated methacrylate copolymer, basicbutylated methacrylate copolymer (Eudragit® E) or poly(methacrylicacid), and may alternatively include hydration-responsive polymernetworks such as hydrogels. The responsive release component maycomprise a percentage of shell portion that is based on the degree ofprotection the API requires, its potential range of action, and theintended trigger conditions. The release responsive component cancomprise from about 1% to about 100% of the shell portion (100% wherethe release responsive component can also act as a stabilizingcomponent). Additionally, the percentage of release responsive componentin the shell portion can be from about 1% to 50%, from about 1% to 25%,and from about 1% to about 10%. In some instances, the releaseresponsive component can be used in a very small fraction where itsaction is dramatic enough to affect the morphology of the core/shellparticle. For any of the above percentages of release responsivecomponent, the balance of the shell portion may comprise one or morehydrophobic matrix components.

In any of the embodiments described herein, the microcapsules of thecomposition may comprise a particle diameter of from about 50 μm toabout 500 μm, from about 100 μm to about 400 μm, from about 150 μm toabout 350 μm, or from about 200 μm to about 300 μm. In anotherembodiment, the microcapsules of the composition may comprise a meanparticle diameter of from about 50 μm to about 500 μm, from about 100 μmto about 400 μm, from about 150 μm to about 350 μm, or from about 200 μmto about 300 μm.

For any of the embodiments described herein, relatively tight particlesize distributions may be preferred. Such particle size distributionsbenefit from the lack of “fines.” Particle fines are small particlesleft over from a manufacturing process. Their small effective surfacearea results in faster dissolution rates. As used herein, the term“fines” refers to particulates having a particle size at or below 10% ofthe mean particle size diameter. Accordingly, formulations havingparticle fines are not substantially monodisperse and may not providethe desired dissolution properties and/or bioavailability. Thus, atleast 80%, and in some instances at least 90%, and in other instancesabout 100% of the microcapsules in a composition have a particlediameter that deviates from the mean particle diameter by about 25% toabout 1%, by about 20% to about 2%, by about 15% to about 5%, andgenerally 10% or less, thus allowing for precise control of releaseproperties.

The embodiments of the present composition described herein may providefor extended release and/or immediate release profiles. In oneembodiment, the present composition is capable of mitigating release ofthe API during the first two minutes in an oral environment and uponencountering an acidic environment, such as in the stomach andgastrointestinal tract, providing an accelerated release with fulldissolution of the API at 30 minutes.

In one particular embodiment, the present composition comprises aplurality of microcapsules, each microcapsule having a core componentcomprising about from about 2.5% to about 15% of prednisone and about85% to about 97.5% of PEG 2000 or 6000, and a shell component comprisingabout 10-20% Eudragit® E PO, about 80-90% stearic acid, and optionallyabout 10% beeswax. Alternatively, in this embodiment, the shellcomponent may comprise about 50-70% carnauba wax, 10-20% beeswax, 5-10%stearic acid, and 5-10% Eudragit® E PO.

In another particular embodiment, the present composition comprises aplurality of microcapsules having a core component comprising about2.5-20% ritonavir and about 80-97.5% PEG 2000 or 6000 and a shellcomponent comprising about 10-20% Eudragit® E PO, about 80% stearicacid, and optionally about 10% beeswax.

The composition of any of the above embodiments may be provided in avariety of formats including liquid suspensions, chewable tablets, andeffervescent tablets.

The present disclosure further provides methods for producing thecompositions described herein. In one embodiment, the method comprisesthe following steps: (1) dissolving the API in ethanol; (2) co-meltingthe API-ethanol mixture with molten excipient to provide a core portion;(3) co-melting a stabilizing component with a release responsivecomponent to form a shell portion; (4) forming microcapsules from thecore portion and shell portion using precision particle fabrication. Theprecision particle fabrication (PPF) is described in more detail in U.S.Pat. No. 6,669,961, which is incorporated herein by reference in itsentirety. Briefly, in PPF, a core portion solution is sprayed through anozzle with (i) vibrational excitation to produce uniform droplets, (ii)an annular shell solution which blankets the core component, and (iii) astabilizing air stream to reduce the diameter of the exiting jet.

EXAMPLES

In the following Examples, ORB-101 refers to an exemplary composition ofthe present disclosure wherein the API is prednisone and ORB-102 refersto an exemplary composition of the present disclosure wherein the API isritonavir.

Poorly Water-Soluble APIs can be Microencapsulated at High Drug Loadingsby Utilizing Solid Dispersion Techniques

Traditional delivery approaches for prednisone and ritonavir eitherinvolve tableting or syrup/suspension formulations, as these allow highdrug loading and immediate bioavailability. The major drawbackassociated with these formulations is palatability. Both prednisone andritonavir are exceptionally foul-tasting, which makes oraladministration unpleasant or even unattainable in pediatric populations,as even a small fraction of drug on the surface of a tablet, ordispersed freely in a syrup, is detectable by the gustatory system.Moreover, there is an increasing demand for novel formulations that cancompletely taste-mask drugs such as prednisone and ritonavir withoutsacrificing immediate bioavailability.

To this end, a pre-formulation solid dispersion of the API in 100%ethanol was created and then added to a hydrophilic excipient in moltenform, which addressed the processibility and dissolution aspects,respectively. When heated for prolonged periods, ethanol was vaporized,leaving a uniform suspension of the API in melted excipient.Differential Scanning Calorimetry (DSC) thermograms generated on the rawmaterials and formulations demonstrated that the dispersion process waseffective in creating amorphous distribution of drug in the solutions(FIG. 1). Moreover, these solutions were then ready to process via PPFas the cores for ORB-101 and ORB-102.

Drug-Free Shells can be Made from Lipids and/or pH-Responsive MaterialsUsing a Single Step with PPF.

Once formulation development on the “core” solutions was complete,“shell” materials for microscopic capsule formation were investigated.Three commonly used oral excipients were investigated: two lipids and apH-responsive ionic copolymer. The main goal of this Example was todetermine which shell materials could provide a protective coating forthe ORB-101 and ORB-102 cores, and yield a fine, dry, flowable powderafter the water-free microencapsulation process. Specifically, differentcombinations of the drug-free excipients were melted and co-flowedaround the drug-rich core solutions in a custom PPF nozzle, whichyielded microcapsules between 200 and 300 μm (FIG. 2). Typical capsuleformulations with a mean particle diameter of 200 μm attained drugloadings of prednisone and ritonavir at 4.8±0.3% w/w and 6.5±0.2% w/w,respectively.

Core-Shell ORB-101 and ORB-102 Capsules Exhibit Delayed and AcceleratedRelease Kinetics in Neutral and Acidic Environments, Respectively.

The ORB-101 and ORB-102 formulations were iteratively tested fordissolution properties in a United States Pharmacopeia (USP) Type IIapparatus at 37° C. in both neutral and acidic environments. Particularattention was paid to the release kinetics of the formulation during thefirst 2 minutes, as this is the most critical period for indicatingtaste-masking ability in vitro. The prednisone and ritonavirmicrocapsules ORB-101 and ORB-102 were also compared to commerciallyavailable liquid formulations of the drugs, prednisone and Norvir,respectively.

The results indicated that in neutral environments (similar to the oralcavity), the Orbis formulations were capable of mitigating API releaseduring the first 2 minutes, and providing slow release afterwards. Inacidic conditions (similar to the stomach and gastrointestinal tract),the formulations also mitigated API release during the first 2 minutes,but rapidly released drug thereafter. These kinetic properties, whenconsidered in conjunction with one another (FIG. 3), demonstrate thatthe ORB-101 and ORB-202 formulations have the ability to mitigate drugrelease for the first 2 minutes in an oral environment, but then releasedrug in an accelerated fashion once reaching the lower pH environment ofthe stomach and GI tract. Specifically, at 2 minutes in a neutralenvironment, the ORB-101 and ORB-102 formulations had released 55 and92% less API than the prednisone and ritonavir liquids, respectively.Importantly, both syrup formulations of prednisone and ritonavir reachedfull dissolution by 30 minutes, with over 90% cumulative release by 5minutes.

ORB-101 and ORB-102 Formulations are Shelf-Stable for At Least One MonthWithout Additional Drug Stabilization.

Samples of core-shell prednisone and ritonavir capsules were retained insealed glass vials at 25° C. for one month and then re-tested theirdissolution behavior. Not only did the capsules have nearly identicalrelease kinetics in neutral conditions compared to freshly-fabricatedsamples, they also displayed the previously-seen accelerated release inthe acidic medium (FIG. 4). Moreover, the formulations displayedinherent shelf stability without any concerted stabilization efforts.

Dissolution Profiles of Various Microcapsule Formulations of Prednisoneand Ritonavir

The formulations in Table 1 were produced using PPF as described above.The dissolution studies for Formulations 1, 2, 5, and 6 were performedin 900 mL of a pH 2 solution using a USP Type II apparatus at 37° C. and75 rpm. The dissolution studies for Formulations 3, 4, and 7 wereperformed in both 900 mL of a pH 7.4 and 900 mL of a pH 2 solution usinga USP Type II apparatus at 37° C. and 75 rpm. The dissolution wasperformed in neutral conditions (pH 7.4) for the first 2 minutes,followed by the acidic conditions (pH 2) for 5-30 minutes. Thedissolution profiles for Formulations 1-4 and 5-7 were compared toPrednisone syrup and Ritonavir syrup, respectively. The dissolutionresults are shown in FIG. 5.

TABLE 1 Prednisone and Ritonavir Formulations Core Shell Formulation (%w/w) (% w/w) 1 Prednisone - 3.0 Carnauba Wax - 100 PEG 2000 2Prednisone - 2.7 Carnauba Wax - 64 PEG 2000 Beeswax - 16 Stearic Acid -10 Eudragit ® E PO - 10 3 Prednisone - 2.7 Stearic Acid - 80 PEG 2000Eudragit ® E PO - 20 4 Prednisone - 1.0 Stearic Acid - 80 PEG 6000Eudragit ® E PO - 20 5 Ritonavir - 10.8 Carnauba Wax - 100 PEG 2000 6Ritonavir - 19.3 Carnauba Wax - 80 PEG 2000 Beeswax - 10 Eudragit ® EPO - 10 7 Ritonavir - 6.7 Stearic Acid - 80 PEG 2000 Eudragit ® E PO -20

Therefore, the present invention is well adapted to attain the ends andadvantages mentioned as well as those that are inherent therein. Whilenumerous changes may be made by those skilled in the art, such changesare encompassed within the spirit of this invention as illustrated, inpart, by the appended claims.

What is claimed is:
 1. A composition comprising: a microcapsulecomprising a core portion and a shell portion, wherein the core portioncomprises an active pharmaceutical ingredient and a hydrophilicexcipient, wherein the shell portion comprises a mixture of ahydrophobic matrix and from about 1% to 25% by weight of a pH-responsivematerial, wherein the pH-responsive material is insoluble at a pH ofgreater than 5.0 or is otherwise insoluble in saliva and is soluble at apH of less than 5.0, the balance of the shell portion comprising thehydrophobic matrix, wherein the hydrophobic matrix comprises one or morehydrophobic matrix components, wherein at least one of the hydrophobicmatrix components is a wax or a lipid, wherein the shell portionencapsulates the core portion.
 2. The composition of claim 1, whereinthe hydrophilic excipient is one or more selected from the groupconsisting of polyethylene glycol, polyols, and poloxamer and lutrolblock copolymers.
 3. The composition of claim 1, wherein the hydrophilicexcipient is polyethylene glycol.
 4. The composition of claim 3 whereinthe active pharmaceutical ingredient is hydrophobic.
 5. The compositionof claim 1 wherein pH-responsive material is a butylated methacrylatecopolymer.
 6. The composition of claim 1, wherein the one or morehydrophobic matrix components further comprises stearic acid.
 7. Thecomposition of claim 6, wherein the one or more hydrophobic matrixcomponents comprises the wax, and wherein the wax is a combination ofcarnauba wax and beeswax.
 8. The composition of claim 1 wherein thepH-responsive material comprises methacrylate copolymer, butylatedmethacrylate copolymer, basic butylated methacrylate copolymer,poly(methacrylic acid), amino methacrylate copolymer, aminoalkylmethacrylate copolymer, hydroxypropylmethyl cellulose phthalate,hypomellose phthalate, polyacrylate derivative or polymethacrylatederivative, and the hydrophobic matrix comprises a wax, lipid orcombination thereof.
 9. The composition of claim 8, wherein the one ormore hydrophobic matrix components further comprises stearic acid. 10.The composition of claim 9, wherein the one or more hydrophobic matrixcomponents comprises the wax, and wherein the wax is a combination ofcarnauba wax and beeswax.
 11. The composition of claim 10, wherein thepH-responsive material is a butylated methacrylate copolymer.
 12. Thecomposition of claim 2, wherein the pH-responsive material comprises abutylated methacrylate copolymer and the one or more hydrophobic matrixcomponents further comprises stearic acid.
 13. The composition of claim12, wherein the one or more hydrophobic matrix components comprises thewax, and wherein the wax is selected from the group consisting ofcarnauba wax, beeswax, and a combination thereof.
 14. The composition ofclaim 1, wherein the active pharmaceutical ingredient is selected fromthe group consisting of prednisone and ritonavir, and the one or morehydrophobic matrix components comprises a lipid.
 15. The composition ofclaim 14 wherein the pH-responsive material comprises a butylatedmethacrylate copolymer.
 16. The composition of claim 1 comprising aplurality of the microcapsules having a mean particle diameter fromabout 100 μm to about 400 μm wherein at least 80% of the microcapsuleshave a particle diameter within 25% of the mean particle diameter of theplurality of microcapsules.
 17. The composition of claim 1 comprising aplurality of the microcapsules in a liquid suspension.
 18. Thecomposition of claim 1 comprising a plurality of the microcapsulesformulated as a dry powder.
 19. The composition of claim 1 wherein theshell portion comprises from about 1% to 10% by weight of thepH-responsive material.
 20. The composition of claim 1 wherein thehydrophobic matrix further comprises a glycerol fatty acid ester, acellulose ether, or a cellulose ester.
 21. The composition of claim 1wherein the one or more hydrophobic matrix components comprises carnaubawax or glycerol monostearate.
 22. The composition of claim 21 whereinthe one or more hydrophobic matrix components further comprises asorbitan ester.
 23. The composition of claim 21 wherein the one or morehydrophobic matrix components further comprises sorbitan oleate.
 24. Thecomposition of claim 1 wherein the one or more hydrophobic matrixcomponents further comprises a sorbitan ester.
 25. The composition ofclaim 1 wherein the one or more hydrophobic matrix components furthercomprises sorbitan oleate.